Diet-controlled Probiotics Show Promise With Clear Limits
Probiotics are live microorganisms that can confer health benefits when ingested. Potential benefits include improved immune function and digestion. There is, however, significant progress to be made in the field.
Recent research by Whitaker et al. (2025) attempts to address a central limitation of probiotic therapy. Once a probiotic is ingested and integrated into the microbiome, it has proved difficult to modulate the microbe’s abundance. This lack of control gives rise to safety concerns, as uncontrolled microbial overgrowth can destabilize the gut.
The researchers engineered a therapeutic bacterial strain that attempts to address these concerns. Phocaeicola vulgatus was modified such that it can grow effectively only in the presence of porphyran, a carbohydrate found in red seaweed. By doing so, the abundance of P. vulgatus in the microbiome can be controlled by porphyran consumption, like a diet-based on-off switch. The researchers engineered the same bacterium to break down oxalate, lowering levels in the gut and reducing the risk of kidney stones. Taken together, this bacterium should behave as an oxalate-degrading probiotic whose abundance can be adjusted on command via porphyran consumption.
They proceeded by conducting preclinical studies. To do so, they gavaged rats with P. vulgatus engineered with oxalate degradation but not porphyran dependence. These experiments were successful, showing reduced oxalate levels. To assess the porphyran-dependent growth, P. vulgatus engineered with porphyran dependence was tested on mice. The mice were fed porphyran for 28 days, after which porphyran was removed from their diet. As predicted, during the time period mice were consuming porphyran, the abundance of P. vulgatus increased. However, results suggested a significant limitation: after porphyran was removed from the diet, of the 8 mice tested, only 5 of the mice’s P. vulgatus levels dropped back down to baseline. In other words, while the “on” switch to increase abundance worked consistently, the “off” switch was functional in only 62.5% of mice. The “off” switch malfunction was caused by a mutation (a change in DNA) in the porphyran-sensing region that controls growth.
Recent research by Whitaker et al. (2025) attempts to address a central limitation of probiotic therapy. Once a probiotic is ingested and integrated into the microbiome, it has proved difficult to modulate the microbe’s abundance. This lack of control gives rise to safety concerns, as uncontrolled microbial overgrowth can destabilize the gut.
The researchers engineered a therapeutic bacterial strain that attempts to address these concerns. Phocaeicola vulgatus was modified such that it can grow effectively only in the presence of porphyran, a carbohydrate found in red seaweed. By doing so, the abundance of P. vulgatus in the microbiome can be controlled by porphyran consumption, like a diet-based on-off switch. The researchers engineered the same bacterium to break down oxalate, lowering levels in the gut and reducing the risk of kidney stones. Taken together, this bacterium should behave as an oxalate-degrading probiotic whose abundance can be adjusted on command via porphyran consumption.
They proceeded by conducting preclinical studies. To do so, they gavaged rats with P. vulgatus engineered with oxalate degradation but not porphyran dependence. These experiments were successful, showing reduced oxalate levels. To assess the porphyran-dependent growth, P. vulgatus engineered with porphyran dependence was tested on mice. The mice were fed porphyran for 28 days, after which porphyran was removed from their diet. As predicted, during the time period mice were consuming porphyran, the abundance of P. vulgatus increased. However, results suggested a significant limitation: after porphyran was removed from the diet, of the 8 mice tested, only 5 of the mice’s P. vulgatus levels dropped back down to baseline. In other words, while the “on” switch to increase abundance worked consistently, the “off” switch was functional in only 62.5% of mice. The “off” switch malfunction was caused by a mutation (a change in DNA) in the porphyran-sensing region that controls growth.
P. vulgatus primarily colonizes the large intestine
Image Source: Aakash Dhage
To address this, the bacterium was engineered with three independent porphyran-sensing growth switches. For the revised “off” switch to fail, all three switches must independently mutate. This version yielded stronger results: after porphyran was removed from the diet, almost all mice returned to baseline levels of P. vulgatus, and the few that did not had minimal amounts that did not rebound.
Following preclinical trials, the bacterium was tested in humans. The researchers began with healthy volunteers, administering P. vulgatus and feeding porphyran to patients for 2 weeks. Like the mice, removing porphyran from the diet generally led to baseline levels, while the patients that did not return to baseline had very low levels. No serious side effects were observed.
After testing healthy volunteers, the researchers tested the bacterium in humans with enteric hyperoxaluria. These individuals are susceptible to kidney stones due to elevated oxalate levels. The results showed significant limitations. First, the bacteria were not consistently able to integrate into the microbiome of patients. In 5 of the 7 patients in which integration was succession, horizontal gene transfer, an event where bacteria exchange DNA, occurred. In effect, the engineered P. vulgatus lost its function or was outcompeted by other bacteria in the gut. No serious side effects were observed.
Overall, the researchers presented a promising engineered microbial therapeutic that demonstrated some ability to lower oxalate with diet-controlled abundance. However, challenges with colonization, mutations, and horizontal gene transfer demonstrate that much progress remains to be made. With refinement, probiotics whose abundance can be controlled offer promising therapeutic prospects for a range of colonic, neural, metabolic, and immune conditions.
Following preclinical trials, the bacterium was tested in humans. The researchers began with healthy volunteers, administering P. vulgatus and feeding porphyran to patients for 2 weeks. Like the mice, removing porphyran from the diet generally led to baseline levels, while the patients that did not return to baseline had very low levels. No serious side effects were observed.
After testing healthy volunteers, the researchers tested the bacterium in humans with enteric hyperoxaluria. These individuals are susceptible to kidney stones due to elevated oxalate levels. The results showed significant limitations. First, the bacteria were not consistently able to integrate into the microbiome of patients. In 5 of the 7 patients in which integration was succession, horizontal gene transfer, an event where bacteria exchange DNA, occurred. In effect, the engineered P. vulgatus lost its function or was outcompeted by other bacteria in the gut. No serious side effects were observed.
Overall, the researchers presented a promising engineered microbial therapeutic that demonstrated some ability to lower oxalate with diet-controlled abundance. However, challenges with colonization, mutations, and horizontal gene transfer demonstrate that much progress remains to be made. With refinement, probiotics whose abundance can be controlled offer promising therapeutic prospects for a range of colonic, neural, metabolic, and immune conditions.
Featured Image Source: Daily Nouri
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